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Multifunctional Neuroprotective Drugs for the Treatment of Alzheimer's Disease

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Pharmacological Mechanisms in Alzheimer's Therapeutics

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The concept of targeting multiple disease etiologies that lead to cognitive impairment in the neurodegenerative disorder Alzheimer’s disease (AD) is challenging the widely held assumption that “ silver bullet” agents are superior to “ dirty drugs” in drug therapy. Accumulating evidence in the literature suggests that a drug with two or more mechanisms of action targeted at multiple etiologies of the same disease may offer more therapeutic benefit in certain disorders than a drug that targets one disease etiology only. In addition, such multiple mechanism/multifunctional drugs may exhibit a more favorable side effect profile than a polypharmaceutical combination of several drugs that individually target the same disease etiologies than those identified for a single multifunctional drug. In this chapter, we offer a synopsis of therapeutic strategies and novel investigative drugs, developed in our own and other laboratories, which modulate multiple disease targets associated with AD and cognitive impairment disorders.

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References

  • Akk, G., & Steinbach, J. H. (2005). Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site. Journal of. Neuroscience, 25, 1992–2001.

    Article  CAS  PubMed  Google Scholar 

  • Arundine, M., & Tymianski, M. (2004). Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cellular and Molecular Life Sciences, 61, 657–668.

    Article  CAS  PubMed  Google Scholar 

  • Avramovich, Y., Amit, T., & Youdim, M. B. H. (2002). Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloidogenic precursor protein. Journal of Biological Chemistry, 277, 31466–31473.

    Article  CAS  PubMed  Google Scholar 

  • Avramovich-Tirosh, Y., Reznichenko, L., Amit, T., Zheng, H., Fridkin, M., Weinreb, O., et al. (2006). Neurorescue Activity, APP Regulation and Amyloid-β Peptide Reduction by Novel Multi-Functional Brain Permeable Iron- Chelator- Antioxidants, M-30 and Green Tea Polyphenol, EGCG. Current Alzheimers Disease Research (in press).

    Google Scholar 

  • Ben Shachar, D., Kahana, N., Kampel, V., Warshawsky, A., & Youdim, M. B. H. (2004). Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats. Neuropharmacology, 46, 254–263.

    Article  CAS  Google Scholar 

  • Breitner, J. C., Welsh, K. A., Helms, M. J., Gaskell, P. C., Gau, B. A., Roses, A. D., et al. (1995). Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiology of Aging, 16, 523–530.

    Article  CAS  PubMed  Google Scholar 

  • Buxbaum, J. D., Cullen, E. I., & Friedhoff, L. T. (2002). Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients. Frontiers in Bioscience, 1, 50–59.

    Article  Google Scholar 

  • Castagnoli, N, Jr., Petzer, J. P., Steyn, S., Castagnoli, K., Chen, J. F., Schwarzschild, M. A., et al. (2003). Monoamine oxidase B inhibition and neuroprotection: studies on selective adenosine A2A receptor antagonists. Neurology, 61, (11 Suppl. 6), S62–S68.

    CAS  PubMed  Google Scholar 

  • Chen, J. F., Steyn, S., Staal, R., Petzer, J. P., Xu, K., Van Der Schyf, C. J., et al. (2002). 8-(3-Chlorostyryl) caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism. Journal of Biological Chemistry, 277, 36040–36044.

    Article  CAS  PubMed  Google Scholar 

  • Christiaans, J. A. M., & Timmerman, H. (1996). Cardiovascular hybrid drugs: Combination of more than one pharmacological property in one single molecule. European Journal of Pharmaceutical Sciences, 4, 1–22.

    Article  CAS  Google Scholar 

  • Chung, K. F., & Adcock, I. M. (2004). Combination therapy of long-acting beta2-adrenoceptor agonists and corticosteroids for asthma. Treatments in Respiratory Medicine, 3, 279–289.

    Article  CAS  PubMed  Google Scholar 

  • Collins, F., & Lile, J. D. (1989). The role of dihydropyridine-sensitive voltage-gated calcium channels in potassium-mediated neuronal survival. Brain Research, 502, 99–108.

    Article  CAS  PubMed  Google Scholar 

  • Cordle, A., & Landreth, G. (2005). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses. Journal of Neuroscience, 25, 299–307.

    Article  CAS  PubMed  Google Scholar 

  • Dajas-Bailador, F. A., Heimala, K., & Wonnacott, S. (2003). The allosteric potentiation of nicotinic acetylcholine receptors by galantamine is transduced into cellular responses in neurons: Ca2+ signals and neurotransmitter release. Molecular Pharmacology, 64, 1217–1226.

    Article  CAS  PubMed  Google Scholar 

  • Dall'Igna, O. P., Porciuncula, L. O., Souza, D. O., Cunha, R. A., & Lara, D. R. (2003). Neuroprotection by caffeine and adenosine A2A receptor blockade of beta-amyloid neurotoxicity. British Journal of Pharmacology, 138, 1207–1209.

    Article  CAS  PubMed  Google Scholar 

  • Dall'Igna, O. P., Souza, D. O., & Lara, D. R. (2004). Caffeine as a neuroprotective adenosine receptor antagonist. Annals of Pharmacotherapy, 38, 717–718.

    Article  PubMed  Google Scholar 

  • Deane, R., Du Yan, S., Submamaryan, R. K., LaRue, B., Jovanovic, S., Hogg, E., et al. (2003). RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nature Medicine, 9, 907–913.

    Article  CAS  PubMed  Google Scholar 

  • Dengiz, A. N., & Kershaw, P. (2004). The clinical efficacy and safety of galantamine in the treatment of Alzheimer's disease. CNS Spectrums. 9, 377–392.

    PubMed  Google Scholar 

  • Farlow, M. R. (2004). NMDA receptor antagonists. A new therapeutic approach for Alzheimer's disease. Geriatrics, 59, 22–27.

    PubMed  Google Scholar 

  • Fassbender, K., Simons, M., Bergmann, C., Stroick, M., Lutjohann, D., Keller, P., et al. (2001). Simvastatin strongly reduces levels of Alzheimer's disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proceedings of the National Academy of Sciences U S A, 98, 5856–5861.

    Article  CAS  Google Scholar 

  • Floden, A. M., Li, S., & Combs, C. K. (2005). Beta-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor alpha and NMDA receptors. Journal of Neuroscence, 25, 2566–2575.

    Article  CAS  Google Scholar 

  • Francis, P. T., Palmer, A. M., Snape, M., & Wilcock, G. K. (1999). The cholinergic hypothesis of Alzheimer's disease: a review of progress. Journal of Neurology, Neurosurgery, and Psychiatry, 66, 137–147.

    Article  CAS  PubMed  Google Scholar 

  • Friedhoff, L. T., Cullen, E. I., Geoghagen, N. S., & Buxbaum, J. D. (2001). Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide. International Journal of Neuropsychopharmacology, 4, 127–130.

    CAS  PubMed  Google Scholar 

  • Gal, S., Zheng, H., Fridkin, M., & Youdim, M. B. H. (2005). Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases, II; in vivo selective brain monoamine oxidase inhibition and prevention of MPTP induced striatal dopamine depletion. Journal of Neurochemistry, 95, 79–88.

    Article  CAS  PubMed  Google Scholar 

  • Geldenhuys, W. J., Malan, S. F., Bloomquist, J. R., Marchand, A. P., & Van der Schyf, C. J. (2005). Pharmacology and structure-activity relationships of bioactive polycyclic cage compounds: a focus on pentacycloundecane derivatives. Medical Research Reviews, 25, 21–48.

    Article  CAS  Google Scholar 

  • Geldenhuys, W. J., Malan, S. F., Bloomquist, J. R., and Van der Schyf, C. J. (2007). Structure-activity relationships of pentacycloundecylamines at the N-methly-D-aspartate receptor. Bioorg. Med. Chem, 15, 1525–1532.

    Article  CAS  PubMed  Google Scholar 

  • Gerriets, T., Stolz, E., Walberer, M., Kaps, M., Bachmann, G., & Fisher, M. (2003). Neuroprotective effects of MK-801 in different rat stroke models for permanent middle cerebral artery occlusion: adverse effects of hypothalamic damage and strategies for its avoidance. Stroke, 34, 2234–2239.

    Article  CAS  PubMed  Google Scholar 

  • Goruglu, A., Kins, T., Cobanoglu, S., Unal, F., Izgi, N. I., Yanik, B., et al. (2000). Reduction of edema and infarction by Memantine and MK-801 after focal cerebral ischaemia and reperfusion in rat. Acta Neurochirurgica (Wien), 142, 1287–1292.

    Article  Google Scholar 

  • Green, R. A., Odergren, T., & Ashwood, T. (2003). Animal models of stroke: do they have value for discovering neuroprotective agents? Trends in Pharmacological. Sciences, 24, 402–408.

    Article  CAS  Google Scholar 

  • Greenblatt, H. M., Kryger, G., Lewis, T., Silman, I., & Sussman, J. L. (1999). Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 Å resolution. FEBS Letters. 463, 321–326.

    Article  CAS  PubMed  Google Scholar 

  • Gurwitz, J. H. (2004). Polypharmacy: a new paradigm for quality drug therapy in the elderly? Archives of Internal Medicine, 164, 1957–1959.

    Article  PubMed  Google Scholar 

  • Hernandez-Pineda, R., Chow, A., Amarillo, Y., Moreno, H., Saganich, M., Vega-Saenz de Miera, E. C., et al. (1999). Kv3.1-Kv3.2 channels underlie a high-voltage-activating component of the delayed rectifier K+ current in projecting neurons from the globus pallidus. Journal of Neurophysiology, 82, 1512–1528.

    CAS  PubMed  Google Scholar 

  • Horn, J., de Haan, R. J., Vermeulen, M., Luiten, P. G., & Limburg, M. (2001). Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke, 32, 2433–2438.

    Article  CAS  PubMed  Google Scholar 

  • Hynd, M. R., Scott, H. L., & Dodd, P. R. (2004). Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. Neurochemistry International, 45, 583–595.

    Article  CAS  PubMed  Google Scholar 

  • Jain, K. K. (2000). Evaluation of memantine for neuroprotection in dementia. Expert Opinion in Investigational Drugs, 9, 1397–1406.

    Article  CAS  Google Scholar 

  • Kadaba, P. K. (2003). Rational drug design and the discovery of the delta2–1, 2, 3-triazolines, a unique class of anticonvulsant and antiischemic agents. Current Medicinal Chemistry, 10, 2081–2108.

    Article  CAS  PubMed  Google Scholar 

  • Keith, C. T., Borisy, A. A., & Stockwell, B. R. (2005). Multicomponent therapeutics for networked systems. Nature Reviews Drug Discovery, 4, 71–78.

    Article  CAS  PubMed  Google Scholar 

  • Kemp, J. A., & McKernan, R. M. (2002). NMDA receptor pathways as drug targets. Nature Neuroscience, 5(Suppl.), 1039–1042.

    Article  CAS  PubMed  Google Scholar 

  • Kiewert, C., Hartmann, J., Stoll, J., Thekkumkaa, T. J., Van der Schyt, C. J., Klein, J. NGP1–01 is a brain-permeable dual blocker of neuronal voltage- and ligand-operated clacium channels, Neurochem Res. 2006, 31, 503–508.

    Article  CAS  Google Scholar 

  • Lipton, P. (1999). Ischemic cell death in brain neurons. Physiological Reviews, 79, 1431–1568.

    CAS  PubMed  Google Scholar 

  • Maia, L., & de Mendonca, A. (2002). Does caffeine intake protect from Alzheimer's disease? European Journal of Neurology, 9, 377–382.

    Article  CAS  PubMed  Google Scholar 

  • Malan, S. F., Dyason, K., Wagenaar, B., Van Der Walt, J. J., & Van Der Schyf, C. J. (2003) The structure and ion channel activity of 6-benzylamino-3-hydroxyhexa- cyclo [6.5.0.03, 7.04, 12.05, 10.09, 13]tridecane. Archiv der Pharmazie, 336, 127–133.

    Article  CAS  PubMed  Google Scholar 

  • Malan, S. F., Van der Walt, J. J., & Van der Schyf C. J. (2000). Structure-activity relationships of polycyclic aromatic amines with calcium channel blocking activity. Archiv der Pharmazie, 333, 10–16.

    Article  CAS  PubMed  Google Scholar 

  • Marco, J. L., de los Rios, C., Garcia, A. G., Villarroya, M., Carreiras, M. C., Martins, C., et al. (2004). Synthesis, biological evaluation and molecular modelling of diversely functionalized heterocyclic derivatives as inhibitors of acetylcholinesterase/butyrylcholinesterase and modulators of Ca2+ channels and nicotinic receptors. Bioorganic and Medicinal Chemistry, 12, 2199–2218.

    Article  CAS  PubMed  Google Scholar 

  • Menge, T., Hartung, H. P., & Stuve, O. (2005). Opinion: Statins - a cure-all for the brain? Nature Reviews Neuroscience, 6, 325–331.

    Article  CAS  PubMed  Google Scholar 

  • Moriguchi, S., Marszalec, W., Zhao, X., Yeh, J. Z., & Narahashi, T. (2003). Potentiation of N-methyl-D-aspartate-induced currents by the nootropic drug nefiracetam in rat cortical neurons. Journal of Pharmacology and Experimental Therapeutics, 307, 160–167.

    Article  CAS  PubMed  Google Scholar 

  • Moriguchi, S., Marszalec, W., Zhao, X., Yeh, J. Z., & Narahashi, T. (2004). Mechanism of action of galantamine on N-methyl-D-aspartate receptors in rat cortical neurons. Journal of Pharmacology and Experimental Therapeutics, 310, 933–942.

    Article  CAS  PubMed  Google Scholar 

  • Morphy, R., Kay, C., & Rankovic, Z. (2004). From magic bullets to designed multiple ligands. Drug Discovery Today, 9, 641–651.

    Article  CAS  PubMed  Google Scholar 

  • Nan, F., Bzdega, T., Pshenichkin, S., Wroblewski, J. T., Wroblewska, B., Neale, J. H., et al. (2000). Dual function glutamate-related ligands: discovery of a novel, potent inhibitor of glutamate carboxypeptidase II possessing mGluR3 agonist activity. Journal of Medicinal Chemistry, 43, 772–777.

    Article  CAS  PubMed  Google Scholar 

  • Narahashi, T., Moriguchi, S., Zhao, X., Marszalec, W., & Yeh, J. Z. (2004). Mechanisms of action of cognitive enhancers on neuroreceptors. Biological and Pharmaceutical Bulletin, 27, 1701–1706.

    Article  CAS  PubMed  Google Scholar 

  • Nicoletti, F., Bruno, V., Copani, A., Casabona, G., & Knopfel, T. (1996). Metabotropic glutamate receptors: a new target for the therapy of neurodegenerative disorders? Trends in Neurosciences, 19, 267–271.

    Article  CAS  PubMed  Google Scholar 

  • Nishizaki, T., Matsuoka, T., Nomura, T., Sumikawa, K., Shiotani, T., Watabe, S., et al. (1998). Nefiracetam modulates acetylcholine receptor currents via two different signal transduction pathways. Molecular Pharmacology, 53, 1–5.

    CAS  PubMed  Google Scholar 

  • O'Neill, M. J., Bath, C. P., Dell, C. P., Hicks, C. A., Gilmore, J., Ambler, S. J., et al. (1997). Effects of Ca2+ and Na + channel inhibitors in vitro and in global cerebral ischaemia in vivo. European Journal of Pharmacology, 332, 121–131.

    Article  PubMed  Google Scholar 

  • Orozco, C., de Los Rios, C., Arias, E., Leon, R., Garcia, A. G., Marco, J. L., et al. (2004), ITH4012 (ethyl 5-amino-6, 7, 8, 9-tetrahydro-2-methyl-4-phenylbenzol[1, 8] naphthyridine-3-carboxylate), a novel acetylcholinesterase inhibitor with “calcium promotor” and neuroprotective properties. Journal of Pharmacology and Experimental Therapeutics, 310, 987–994.

    Article  CAS  PubMed  Google Scholar 

  • Ovbiagele, B., Kidwell, C. S., Starkman, S., & Saver, J. L. (2003). Potential role of neuroprotective agents in the treatment of patients with acute ischemic stroke. Current Treatment Options in Cardiovascular Medicine, 5, 441–449.

    Article  PubMed  Google Scholar 

  • Oyaizu, M., & Narahashi, T. (1999). Modulation of the neuronal nicotinic acetylcholine receptor-channel by the nootropic drug nefiracetam. Brain Research, 822, 72–79.

    Article  CAS  PubMed  Google Scholar 

  • Pahan, K., Sheikh, F. G., Namboodiri, A. M., & Singh, I. (1997). Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. Journal of Clinical Investigation, 100, 2671–2679.

    Article  CAS  PubMed  Google Scholar 

  • Parsons, C. G., Danysz, W., & Quack, G. (1999). Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist–a review of preclinical data. Neuropharmacology, 38, 735–767.

    Article  CAS  PubMed  Google Scholar 

  • Petzer, J. P., Steyn, S., Castagnoli, K. P., Chen, J. F., Schwarzschild, M. A., Van der Schyf, C. J., et al. (2003). Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists. Bioorganic and Medicinal Chemistry, 11, 1299–1310.

    Article  CAS  PubMed  Google Scholar 

  • Prediger, R. D., Batista, L. C., & Takahashi, R. N. (2005). Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats. Involvement of adenosine A1 and A2A receptors. Neurobiology of Aging, 26, 957–964.

    Article  CAS  PubMed  Google Scholar 

  • Rami, A., & Krieglstein, J. (1994). Neuronal protective effects of calcium antagonists in cerebral ischemia. Life Sciences, 55, 2105–2113.

    Article  CAS  PubMed  Google Scholar 

  • Reisberg, B., Doody, R., Stoffler, A., Schmitt, F., Ferris, S., & Mobius, H. J. (2003). Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. New England Journal of Medicine, 348, 1333–13341.

    Article  CAS  PubMed  Google Scholar 

  • Rich, J. B., Rasmusson, D. X., Folstein, M. F., Carson, K. A., Kawas, C., & Brandt, J. (1995). Nonsteroidal anti-inflammatory drugs in Alzheimer's disease. Neurology, 45, 51–55.

    CAS  PubMed  Google Scholar 

  • Riederer, P., Danielczyk, W., & Grunblatt, E. (2004). Monoamine oxidase-B inhibition in Alzheimer's disease. Neurotoxicology, 25, 271–277.

    Article  CAS  PubMed  Google Scholar 

  • Rogers, J., Kirby, L. C., Hempelman, S. R., Berry, D. L., McGeer, P. L., Kaszniak, A. W., et al. (1993). Clinical trial of indomethacin in Alzheimer's disease. Neurology, 43, 1609–1611.

    CAS  PubMed  Google Scholar 

  • Roth, B. L., Sheffler, D. J., & Kroeze, W. K. (2004). Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nature Reviews Drug Discovery, 3, 353–359.

    Article  CAS  PubMed  Google Scholar 

  • Rutherford, G. W., Sangani, P. R., & Kennedy, G. E. (2003). Three- or four- versus two-drug antiretroviral maintenance regimens for HIV infection. Cochrane Database System Review, 4, CD002037.

    Google Scholar 

  • Sagi, Y., Weinstock, M., & Youdim, M. B. H. (2003). Attenuation of MPTP-induced dopaminergic neurotoxicity by TV3326, a cholinesterase-monoamine oxidase inhibitor. Journal of Neurochemistry, 86, 290–297.

    Article  CAS  PubMed  Google Scholar 

  • Sasaki, T., Eguchi, S., & Kiriyama, T. (1971). A facile synthesis of mono-oxa and aza-cage compounds via transanullar cyclizations. Tetrahedron Letters, 2651–2654.

    Google Scholar 

  • Sasaki, T, Kiriyama, E. T., & Hiroaki, O. (1974). Studies on hetero-cage compounds–VI transannular cyclizations in pentacyclo[6.2.1.02, 7.04, 10.05, 9]undecan-3, 6-dione system. Tetrahedron, 30, 2707–2712.

    Article  CAS  Google Scholar 

  • Saura, J., Richards, J. G., & Mahy, N. (1994). Differential age-related changes of MAO-A and MAO-B in mouse brain and peripheral organs. Neurobiology of Aging, 15, 399–408.

    Article  CAS  PubMed  Google Scholar 

  • Schmitt, B., Bernhardt, T., Moeller, H. J., Heuser, I., & Frolich, L. (2004). Combination therapy in Alzheimer's disease: a review of current evidence. CNS Drugs, 18, 827–844.

    Article  CAS  PubMed  Google Scholar 

  • Sramek, J. J., & Cutler, N. R. (1999). Recent developments in the drug treatment of Alzheimer's disease. Drugs and Aging, 14, 359–373.

    Article  CAS  PubMed  Google Scholar 

  • Van der Schyf, C. J., Squier, G. J., & Coetzee, W. A. (1986). Characterization of NGP 1–01, an aromatic polycyclic amine, as a calcium antagonist. Pharmacological Research Communications, 18, 407–417.

    Article  PubMed  Google Scholar 

  • Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., et al. (2001). A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature, 414, 212–216.

    Article  CAS  PubMed  Google Scholar 

  • Wenk, G. L., Rosi, S., McGann, K., Hauss-Wegrzyniak, B. (2002). A nitric oxide-donating flurbiprofen derivative reduces neuroinflammation without interacting with galantamine in the rat. European Journal of Pharmacology, 453, 319–324.

    Article  CAS  PubMed  Google Scholar 

  • Wilkinson, D., & Murray, J. (2001). Galantamine: a randomized, double-blind, dose comparison in patients with Alzheimer's disease. International Journal of Geriatric Psychiatry, 16, 852–857.

    Article  CAS  PubMed  Google Scholar 

  • Youdim, M. B. H. (2006). The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and M30. Current Alzheimer's Disease Research, 3, 541–550.

    Article  CAS  Google Scholar 

  • Youdim, M. B. H., Bar Am, O., Yogev-Falach, M., Weinreb, O., Maruyama, W., Naoi, M., et al. (2005). Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. Journal of Neuroscience Research, 79, 172–179.

    Article  CAS  PubMed  Google Scholar 

  • Youdim, M. B. H., & Buccafusco, J. J. (2005a). CNS Targets for multi-functional drugs in the treatment of Alzheimer's and Parkinson's diseases. Journal of Neural Transmission, 112, 519–537.

    Article  CAS  PubMed  Google Scholar 

  • Youdim, M. B. H., & Buccafusco, J. J. (2005b). Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends in Pharmacological Sciences, 26, 27–35.

    Article  CAS  PubMed  Google Scholar 

  • Youdim, M. B. H., Fridkin, M., & Zheng, H. (2005). Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. Mechanisms of Ageing and Development, 126, 317–326.

    Article  CAS  PubMed  Google Scholar 

  • Zerkak, D., & Dougados, M. (2004). Benefit/risk of combination therapies. Clinical and Experimental Rheumatology, 5(Suppl. 35), S71–S76.

    Google Scholar 

  • Zhao, X., Yeh, J. Z., & Narahashi, T. (2001). Post-stroke dementia. Nootropic drug modulation of neuronal nicotinic acetylcholine receptors. Annals of the New York Academy of Sciences, 939, 179–186.

    Article  CAS  PubMed  Google Scholar 

  • Zheng, H., Gal, S., Weiner, L. M., Bar-Am, O., Warshawsky, A., Fridkin, M., et al. (2005). Novel multifunctional neuroprotective iron chelator-monoamine oxidase drugs for neurodegenerative diseases; I. in vitro studies on iron chelation, antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition. Journal of Neurochemistry, 95, 68–78.

    Article  CAS  PubMed  Google Scholar 

  • Zheng, H., Weiner, L. M., Bar-Am, O., Epsztejn, S., Cabantchik, Z. I., Warshawsky, A., et al. (2005). Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer's, Parkinson's, and other neurodegenerative diseases. Bioorganic and Medicinal Chemistry, 13, 773–783.

    Article  CAS  PubMed  Google Scholar 

  • Zheng H., Youdim, M. B. H., Weiner, L. M., & Fridkin, M. (2005a). Novel potential neuroprotective agents with both iron chelating and amino acid-based derivatives targeting central nervous system neurons. Biochemical Pharmacology, 70, 1642–1652.

    Article  CAS  PubMed  Google Scholar 

  • Zheng, H., Youdim, M. B. H., Weiner, L. M., & Fridkin, M. (2005b). Synthesis and evaluation of peptidic metal chelators for neuroprotection in neurodegenerative diseases. Journal of Peptide Research, 66, 190–203.

    Article  CAS  PubMed  Google Scholar 

  • Zlokovic, B. V. (2005). Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends in Neurosciences, 28, 202–208.

    Article  CAS  PubMed  Google Scholar 

  • Zou, J. Y., & Crews, F. T. (2005). TNFalpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Research, 1034, 11–24.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Northeastern Ohio Universities College of Pharmacy, Rootstown, OH, USA

    Cornelis J. Van der Schyf & Werner J. Geldenhuys

  2. Technion-Rappaport Family-Faculty of Medicine Eve Topf, U.S. National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases, Haifa, Israel

    Moussa B. H. Youdim

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  1. Cornelis J. Van der Schyf
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  2. Werner J. Geldenhuys
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  3. Moussa B. H. Youdim
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Schyf, C.J.V.d., Geldenhuys, W.J., Youdim, M.B.H. (2007). Multifunctional Neuroprotective Drugs for the Treatment of Alzheimer's Disease. In: Pharmacological Mechanisms in Alzheimer's Therapeutics. Springer, New York, NY. https://doi.org/10.1007/978-0-387-71522-3_17

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